In the course of studying the role of chemoattractant receptors in tumor growth and metastasis, we discovered that highly malignant human glioblastoma and anaplastic astrocytoma specimens were stained positively for the formylpeptide receptor FPR, which is normally expressed in myeloid cells and results in their chemotaxis and activation induced by bacterial peptides. Screening of human glioma cell lines revealed that FPR was expressed only in glioma cell lines with a more highly malignant phenotype. FPR expressed in glioblastoma cell lines mediates tumor cell chemotaxis, proliferation and production of an angiogenic factor, vascular endothelial growth factor (VEGF), in response to agonist moleculaes released by necrotic tumor cells. Furthermore, stimulation of FPR in glioblastoma cells also activates the receptor for epidermal growth factor (EGFR) by a signal transduction cascade that increases the phosphorylation of a selected tyrosine residue in the intracellular domain of EGFR and is dependent on G-proteins and controlled by Src tyrosine kinase. This transactivation of EGFR by FPR accounts for approximately 40% of the capacity of FPR to mediate tumor cell migration and activation. Depletion of either FPR or EGFR in tumor cells by small interference (si) RNA each reduced the capacity of the tumor cells to form actively growing tumors in nude mice. However, depletion of both receptors completely abolishes the tumorigenicity of glioblastoma cells. Thus, FPR aberrantly expressed in human glioblastoma by responding to agonist activity produced in the tumor microenvironment cooperates with EGFR to promote rapid tumor progression. These results suggest important molecular targets for the design of anti-glioblastoma therapeutics.